Cancer is one of the most significant causes of death in the world, accounting for approximately 20% of all deaths in humans. The disease, as is commonly well known, can effect persons of all ages, background, and socio-economic status.
There have been a variety of attempts in the prior art which indicate that selenium compounds can exhibit both anticarcinogenic and antimutagenic potential in both in vitro and in vivo systems.
An article by Vernie et al., in Biochem Journal (1979), 180, 213-218 entitled "Studies on the Inhibition of Protein Synthesis by Selenodiglutathione" discloses that GSSeSG is substantially more effective in inhibiting protein synthesis than sodium selenite (Na.sub.2 SeO.sub.3) or oxidized glutathione; more particularly, in a cell-free system derived solely from rats, GSSeSG blocks amino acid incorporation through the inactivation of elongation factor 2 (EF-2). Also, the particular concentrations of GSSeSG utilized (4 .mu.g/ml) are significantly different than the concentrations utilized by applicants. Additionally, neither the binding of aminoacyltRNA to the ribosomes by elongation factor 1, nor the peptidyltransferase reaction, nor the ribosomes per se were affected. The reference further discloses (p218) that the inhibition of protein synthesis of cells in tissue culture opens a new perspective on counteracting tumor cells with selenium-type compounds of the general formula RSSeSR. However, the biphasic effect of the present invention is not taught in the reference.
Another, article by Vernie et al. in Biochemistry, Volume 13, number 2, pgs. 337-391, 1974 entitled "Inhibition of in vitro amino acid incorporation by sodium selenite" discloses that selenite concentrations of 1.1.times.10.sup.-5 M can inhibit EF-2, and the author's earlier work, Vernie et al., Biochem. Biophys. Acta., 414, 283-292 (1975) discloses that EF-2 is the target of the reaction product between Na.sub.2 SeO.sub.3 and glutathione in the inhibiting of amino acid incorporation in vitro. However, the biphasic effect of the present invention is not taught in the reference.
An article by A. M. Watrach et al., in Cancer Letters, 25 (1984) 41-47, entitled "Inhibition of Human Breast Cancer Cells by Selenium" discloses that the parenteral administration of sodium selenite (Na.sub.2 SeO.sub.3) completely inhibits the development of cancerous tumors in mice. The article further indicates that selenium can be transported by the host from a distant administration site to the site of the tumor, where it accumulates within and exerts its inhibiting effect upon cancer cell mitosis. However, the biphasic effect of the present invention is not taught in the reference.
An article by Poirier and Milner, J. Nutr., (1983) entitled "Factors Influencing the Antitumorigenic Properties of Selenium" teaches that the intermediate products of selenium metabolism, such as GSSeSG, are as effective as selenite. However, the article does not disclose the non toxicity of GSSeSG, that GSSeSG is not as mutagenic as Na.sub.2 SeO.sub.3, nor the biphasic effect of the present invention.
An article by Webber et al., BioChemical and Biophysical Research Communications, Vol. 130, No. 2, (1985), 603-609, "Inhibitory Effects of Selenium on the Growth of DU-145 Human Prostate Carcinoma Cells In Vitro" discloses that selenium, when administered as sodium selenite, inhibits the growth of human prostate carcinoma cells in vitro, as well as in other types of cancer cells. The reference further indicates that selenium can inhibit both the initiation and promotion stages of carcinogenesis (page 607) and that selenium inhibits DNA synthesis, as reported by Medina et al., (1984) Cancer Research, 44, 4361-4365. However, the biphasic effect of the present invention is not taught in the reference.
Vendeland et al, "Transport of Selenium as Selenite or Selenomethionine Across Brush-Border Membranes From the Upper Intestines of Rats", The FASEB Journal, Vol. 2, No. 6, Abstract 7692, 1988, p. A1621 (Vendeland et al.), disclose an abstract entitled the "Transport of Selenium As Selenite Or Selenomethionine Across Brush-Bordered Membranes From the Upper Intestines of Rats".
The GSSeSG utilized in the present invention was prepared by modifying a variation in the method of Ganther, reported in Biochemistry, 10:#22, 4089-4098, and improved by Vernie et al., Biochem. Journal (1979), 180-218, page 213.
An article by Milner entitled "Selenium and Carcinogenesis", (1985) American Chemical Society, 267-282 discloses that the anticarcinogenic property of selenium does not appear to be mediated through its association with glutathione peroxidase activity. Selenium is further disclosed as being effective in inhibiting the proliferation of neoplastic cells, and that GSSeSG, or other intermediate compositions which occur during selenium metabolism, are suggested as responsible for the antitumorigenic properties of this element. The diagram on page 278 describes a flow diagram of selenium metabolism which proceeds through GSSeSG.
An article by Medina et al., Cancer Letters, 15 (1982) 301-310, entitled "Uptake and Localization of Selenium-75 in Mammary Epithelial Cell Lines In Vitro" discloses that selenium can inhibit the growth potential of chemical carcinogen-induced tumorigenesis in mice.
A later article by Vernie et al., (1981) Cancer Letters (Shannon, Irel) 14(3), 303-313 entitled "Inhibition of the Growth of Malignant Mouse Lymphoid Cells by Selenodiglutathione and Selenodicysteine" discloses that intraperitoneal injections of GSSeSG or selenodicysteine in mice, which had been previously inoculated with tumor cells, inhibited the tumor growth and increased the life span of the animals as compared with the untreated control mice.
An article by Clement Ip, "Factors influencing the anticarcinogenic efficacy of selenium in DMBA-induced mammary tumorigenesis in rats"; Cancer Research, 41:2683-2686 (1981) teaches that dosages of Na.sub.2 SeO.sub.3 given to rats on low fat diets decrease tumorigenesis, but high fat fed animals did not respond as favorably. The results suggested that selenium has no effect on the proliferation of malignant vs. benign lesions. However, the reference does not teach the use of selenodithiols nor the biphasic effect of the present invention.
An article by Fico et al., "Differential effects of Se on normal and neoplastic canine mammary cells", Cancer Res. 46, 3384-3388 (1986) describes the differential effects of Se on normal and neoplastic canine mammary cells.
An article by Khalil et al entitled "5-Bromodeoxyuridine- and N-Methyl-N-Nitrosourea- Induced Sister Chromatid Exchanges Correlate With Reduced Survival Not Cell Kinetics Of Cultured Human Lymphocytes" disclosed that Sister Chromatid Exchange techniques can be utilized to determine the non-mutagenicity of GSSeSG as compared to other forms of selenium.
Although it is clear that the prior art has attempted a variety of processes which have shown a certain amount of effectiveness in the treatment of carcinogenic cells through the utilization of selenium-containing compounds, these efforts have been unable to effectively destroy cancer cells without also damaging the treated host organism, and do not show a biphasic effect of selenodithiols administered to cells.